In order to provide a meaningful understanding of the complexity and physiology of the nervous system an overview of the various components must be provided which explain their location, their function and overall makeup or construction before one can appreciate the various prior treatments that are currently being used to treat injuries or damage.
The nervous system of an animal coordinates the activity of the muscles, monitors the organs, constructs and processes input from the senses, and initiates actions. In animals with brains, the nervous system also generates and conducts thoughts and emotions. Thus it is the system that animates “animals”. The nervous system consists basically of two types of cells, neurons and glia. Neurons are the primary cells of the nervous system. Glia are secondary cells involved in nourishment and structural support. Rapid signaling within the nervous system occurs by two primary mechanisms: within neuronal nerve fibers by way of action potentials; and between neurons by way of neurotransmitter diffusion across synapses.
The vertebrate central nervous system consists of the brain and spinal cord. These lie in the midline of the body and are protected by the skull and vertebrae respectively. This collection of billions of neurons is arguably the most complex object known. The central nervous system along with the peripheral nervous system comprise a primary division of controls that command all physical activities of a vertebrate. Neurons of the central nervous system affect consciousness and mental activity while spinal extensions of central nervous system neuron pathways affect skeletal muscles and organs in the body. The peripheral system is composed of the somatic nervous system and the autonomic nervous system, the latter being further divided as the sympathetic nervous system, the parasympathetic nervous system and the enteric nervous system. Each of these interacts with various organs, glands or muscles, providing information to and from the central nervous system. The somatic nervous system is the voluntary part of the nervous system that coordinates a body's movements, such as maintaining a particular posture and walking. The autonomic nervous system is the involuntary part of the nervous system where all of the internal maintenance is taken care of. The autonomic nervous system is then divided into the sympathetic division and parasympathetic division. The sympathetic nervous system responds to impending danger or stress, and is responsible for the increase of one's heartbeat and blood pressure, among other physiological changes, along with the sense of excitement he feels. The parasympathetic nervous system, on the other hand, is evident when a person is resting and feels relaxed, and is responsible for such things as the constriction of the pupil, the slowing of the heart, the dilation of the blood vessels, and the stimulation of the digestive and genitourinary systems.
Neurons (also spelled neurones or called nerve cells) are the primary cells of the nervous system. In vertebrates, they are found in the brain, the spinal cord and in the nerves and ganglia of the peripheral nervous system. There are three classes of neurons: afferent neurons, efferent neurons, and interneurons. Afferent neurons convey information from tissues and organs into the central nervous system. Efferent neurons transmit signals from the central nervous system to the effector cells. Interneurons connect neurons within the central nervous system. Many highly specialized types of neurons exist, and these differ widely in appearance. Characteristically, neurons are highly asymmetric in shape. Neurons consist of: the soma, or cell-body, the relatively large central part of the cell between the dendrites and the axon; the axon, a much finer, cable-like projection which may extend tens, hundreds, or even tens of thousands of times the diameter of the soma in length. This is the structure which carries nerve signals away from the neuron. Each neuron has only one axon, but this axon may undergo extensive branching and thereby enable communication with many target cells; and the dendrite, a short, branching arbor of cellular extensions. Each neuron has very many dendrites with profuse dendritic branches. These structures form the main information receiving network for the neuron. Axon and dendrites alike are typically only about a micrometer thick, while the soma is usually about 25 micrometers in diameter and not much larger than the cell nucleus it contains. The axon of a human motoneuron can be over a meter long, reaching from the base of the spine to the toes, while giraffes have single axons running along the whole length of its neck, which is several feet. Neurons communicate with one another and other cells through synapses where the axon tip of one cell impinges upon a dendrite or soma of another, or less commonly to an axon. Neurons of the cortex in mammals, such as the Purkinje cells, can have over 1000 dendrites each, enabling connections with tens of thousands of other cells. Neurons communicate with one another across synapses. This communication is usually chemically mediated by rapid secretion of neurotransmitter molecules. Pre-synaptic neurons (i.e. the neurons which release the neurotransmitter) may produce in the post-synaptic neurons (i.e. the neurons being affected by the neurotransmitter) an electrical stimulation (an electrical excitation) which will spread to the axon hillock generating an action potential which then travels as a wave of electrical excitation along the axon. Arrival of an action potential at the tip of an axon triggers the release of neurotransmitter at a synaptic gap. Neurotransmitters can either stimulate or suppress (inhibit) the electrical excitability of a target cell. An action potential will only be triggered in the target cell if neurotransmitter molecules acting on their post-synaptic receptors cause the cell to reach its threshold potential.
Another less common form of communication between neurons is through electrical synapses mediated by gap junctions. The narrow cross-section of axons and dendrites lessens the metabolic expense of carrying action potentials, although thicker axons convey the impulses more rapidly, generally speaking. Many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables the action potentials to travel faster than in unmyelinated axons of the same diameter whilst simultaneously preventing short circuits amongst intersecting neurons. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier. Multiple sclerosis is a neurological disorder which results from abnormal demyelination of peripheral nerves. Neurons with demyelinated axons do not conduct electrical signals properly.
Neurons and glia make up the two chief cell types of the central nervous system. There are far more glial cells than neurons, and recent experimental results have suggested that glial cells play a vital role in information processing among neurons. Nerve cell bodies stained with basophilic dyes will show numerous microscopic clumps of Nissl substance (named after German psychiatrist and neuropathologist Franz Nissl, 1860-1919), which consists of rough endoplasmic reticulum and associated ribosomes. The prominence of the Nissl substance can be explained by the fact that nerve cells are metabolically very active, and hence are involved in large numbers of protein synthesis. The cell body of a neuron is supported by a complex meshwork of structural proteins called neurofilaments, which are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment, byproduct of synthesis of catecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).
The human brain has about 100 billion (1011) neurons and 100 trillion (1014) connections (synapses) between them. The brain receives sensory input from the spinal cord as well as from its own nerves (e.g., olfactory and optic nerves) and devotes most of its volume (and computational power) to processing its various sensory inputs and initiating appropriate and coordinated motor outputs.
Both the spinal cord and the brain consist of white matter (bundles of axons each coated with a sheath of myelin) and gray matter (masses of the cell bodies and dendrites each covered with synapses). In the spinal cord, the white matter is at the surface, the gray matter inside. In the brain of mammals, this pattern is reversed. However, the brains of “lower” vertebrates like fishes and amphibians have their white matter on the outside of their brain as well as their spinal cord.
Both the spinal cord and brain are covered in three continuous sheets of connective tissue, the meninges. From outside in, these are the dura mater pressed against the bony surface of the interior of the vertebrae and the cranium, the arachnoid and the pia mater. The region between the arachnoid and pia mater is filled with cerebrospinal fluid (CSF).
The cells of the central nervous system are bathed in a fluid that differs from that serving as the ECF of the cells in the rest of the body. The fluid that leaves the capillaries in the brain contains far less protein than “normal” because of the blood-brain barrier, a system of tight junctions between the endothelial cells of the capillaries. This barrier creates problems in medicine as it prevents many therapeutic drugs from reaching the brain. Cerebrospinal fluid (CSF), is a secretion of the choroid plexus. CSF flows uninterrupted throughout the central nervous system through the central cerebrospinal canal of the spinal cord and through an interconnected system of four ventricles in the brain. CSF returns to the blood through veins draining the brain.
In the spinal cord there are thirty-one pairs of spinal nerves which arise along the spinal cord. These are “mixed” nerves because each contain both sensory and motor axons. However, within the spinal column, all the sensory axons pass into the dorsal root ganglion where their cell bodies are located and then on into the spinal cord itself and all the motor axons pass into the ventral roots before uniting with the sensory axons to form the mixed nerves. The spinal cord carries out two main functions: it connects a large part of the peripheral nervous system to the brain. Information (nerve impulses) reaching the spinal cord through sensory neurons is transmitted up into the brain. Signals arising in the motor areas of the brain travel back down the cord and leave in the motor neurons and the spinal cord also acts as a minor coordinating center responsible for some simple reflexes like the withdrawal reflex. The interneurons carrying impulses to and from specific receptors and effectors are grouped together in spinal tracts. Impulses reaching the spinal cord from the left side of the body eventually pass over to tracts running up to the right side of the brain and vice versa. In some cases this crossing over occurs as soon as the impulses enter the cord. In other cases, it does not take place until the tracts enter the brain itself.
The brain of all vertebrates develops from three swellings at the anterior end of the neural canal of the embryo. From front to back these develop into the forebrain (also known as the prosencephalon), the midbrain (mesencephalon) and the hindbrain (rhombencephalon). The brain receives nerve impulses from the spinal cord and 12 pairs of cranial nerves. Some of the cranial nerves are “mixed”, containing both sensory and motor axons, some, e.g., the optic and olfactory nerves (numbers I and II) contain sensory axons only, while some, e.g. number III that controls eyeball muscles, contain motor axons only. The main structures of the hindbrain are the medulla oblongata, the pons and the cerebellum. The medulla looks like a swollen tip to the spinal cord. Nerve impulses arising here rhythmically stimulate the intercostal muscles and diaphragm—making breathing possible, regulate heartbeat, and regulate the diameter of arterioles thus adjusting blood flow.
The pons seems to serve as a relay station carrying signals from various parts of the cerebral cortex to the cerebellum. Nerve impulses coming from the eyes, ears, and touch receptors are sent on the cerebellum. The pons also participates in the reflexes that regulate breathing. The reticular formation is a region running through the middle of the hindbrain (and on into the midbrain). It receives sensory input (e.g., sound) from higher in the brain and passes these back up to the thalamus. The reticular formation is involved in sleep, arousal (and vomiting).
The cerebellum consists of two deeply-convoluted hemispheres. Although it represents only 10% of the weight of the brain, it contains as many neurons as all the rest of the brain combined. Its most clearly-understood function is to coordinate body movements. People with damage to their cerebellum are able to perceive the world as before and to contract their muscles, but their motions are jerky and uncoordinated. So the cerebellum appears to be a center for learning motor skills (implicit memory). Laboratory studies have demonstrated both long-term potentiation (LTP) and long-term depression (LTD) in the cerebellum.
The midbrain occupies only a small region in humans (it is relatively much larger in “lower” vertebrates). It has three primary features: the reticular formation: collects input from higher brain centers and passes it on to motor neurons; the substantia nigra: helps “smooth” out body movements; damage to the substantia nigra causes Parkinson's disease; and the ventral tegmental area (VTA): packed with dopamine-releasing neurons that synapse deep within the forebrain. The VTA seems to be involved in pleasure.
The human forebrain is made up of a pair of large cerebral hemispheres, called the telencephalon. Because of crossing over of the spinal tracts, the left hemisphere of the forebrain deals with the right side of the body and vice versa and a group of unpaired structures located deep within the cerebrum, called the diencephalon. The diencephalon has 4 primary structures: the thalamus where all sensory input (except for olfaction) passes through it on the way up to the somatic-sensory regions of the cerebral cortex and then returns to it from there and signals from the cerebellum pass through it on the way to the motor areas of the cerebral cortex; the Lateral geniculate nucleus (LGN) where all signals entering the brain from the optic nerves enter the LGN and undergo some processing before moving on the various visual areas of the cerebral cortex. The hypothalamus is the seat of the autonomic nervous system (damage to the hypothalamus is quickly fatal as the normal homeostasis of body temperature, blood chemistry, etc. goes out of control). It is the source of eight hormones, two of which pass into the posterior lobe of the pituitary gland. The Posterior lobe of the pituitary which receives antidiuretic hormone (ADH) and oxytocin from the hypothalamus and releases them into the blood. Each hemisphere of the cerebrum is subdivided into four lobes visible from the outside: the frontal, the parietal, the occipital and the temporal. Hidden beneath these regions of cerebral cortex are the olfactory bulbs, the striatum, the nucleus accumbens (NA) and the limbic system. The olfactory bulbs receive input from the olfactory epithelia. The striatum receives input from the frontal lobes and also from the limbic system (below) at its base is the nucleus accumbens (NA). The pleasurable (and addictive) effects of amphetamines, cocaine, and perhaps other psychoactive drugs seem to depend on their producing increasing levels of dopamine at the synapses in the nucleus accumbens (as well as the VTA). The limbic system receives input from various association areas in the cerebral cortex and passes signals on to the nucleus accumbens. The limbic system is made up of the hippocampus, it is essential for the formation of long-term memories; and the amygdala. The amygdala appears to be a center of emotions (e.g., fear). It sends signals to the hypothalamus and medulla which can activate the flight or fight response of the autonomic nervous system. In rats, at least, the amygdala contains receptors for vasopressin whose activation increases aggressiveness and other signs of the flight or fight response; and oxytocin whose activation lessens the signs of stress. The amygdala receives a rich supply of signals from the olfactory system, and this may account for the powerful effect that odor has on emotions (and evoking memories).
Damage to the nervous system can be caused by infectious diseases or trauma. In the brain strokes, tumors as well as trauma injuries can result in damage. The onset of neural or nerve damage can be and often is progressive in the scope and rate of the degenerative condition.
U.S. Pat. No. 6,544,987 entitled “Compounds, Compositions and Methods for Stimulating Neuronal Growth and Elongation” assigned to Pfizer Inc. suggested inhibiting rotomase enzyme activity associated with binding proteins with an affinity for FKBP—type imminophilins could be a useful medicament providing methods to treat neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries.
Earlier findings of Peter Wehling in U.S. Pat. No. 5,173,295 entitled “Method of Enhancing the Regeneration of Injured Nerves and Adhesive Pharmaceutical Formulation Therefor” found the regeneration of injured nerves is enhanced by supplying collagenase to the zone of injury of the nerve. Growth of nerve sprouts over the zone of injury is aided by the presence of effective amounts of collagenase during the regeneration process. If the nerve has been severed, collagenase is supplied to the ends of the proximal and distal stumps. A nerve graft may be interposed between the stumps. Natural fibrin has been used as glue to join nerve stumps, and collagenase is effective when used in admixture with fibrin.
In U.S. Pat. No. 4,868,161 entitled “Method for Promoting Nerve Regeneration” Eugene Roberts discovered a method for promoting regeneration of damaged nerve tissue, comprising administering, either alone or in combination, an effective amount of an antimitotic agent or a proton-withdrawing buffer to the damage site. Antimitotic agents reduce the rate of growth of glial cells, and buffers facilitate the growth of nerve tissue and inhibit glial cell growth. Referred antimitotic agents are cytosine arabinoside, 5-fluorouracil, and hydroxyurea. Preferred buffers are TREA and HEPES. Compositions are disclosed which include antimitotic agent, buffer, and an oxygen-supplying compound, such as hydrogen peroxide.
In U.S. Pat. No. 6,881,409 entitled “Compositions and Methods for Promoting Nerve Regeneration”, Bruce C. Gold stated, I have discovered that geldanamycin and FK506 stimulate nerve regeneration via a common mechanism. Both compounds bind to polypeptide components of steroid receptor complexes, hsp90 and FKBP52, respectively. These and other compounds that cause hsp90 dissociation from steroid receptor complexes or that block association of hsp90 with steroid receptor complexes stimulate nerve cell growth and promote nerve regeneration. Such compounds can act directly by binding to hsp90 (as in the case of geldanamycin) or indirectly by binding to another polypeptide in the steroid receptor complex (as in the case of FK506 binding of FKBP52).
According to each aspect of these prior art inventions, methods of stimulating nerve cell growth in a mammal are provided that include administering a pharmaceutical composition.
Others have suggested surgical implants of regenerative electrical stimulation to stimulate regeneration and or healing of damaged nerve tissue as is found in U.S. Pat. No. 5,314,457.
The benefits of solving the mystery of repairing damaged or degenerative conditions involving the nervous system are enormous. It appears that a solution most clearly resides in the stimulation of nerve cells or neurons, generally. More specifically in achieving a systemic release of growth factors within these cells including, but not limited to activation of proteins and or stem cells in the region of trauma or injury to the nerve cells or tissue.
It is therefore an object of the present invention to provide a means to stimulate regeneration of damaged or degenerating neurons or nerve cells in nerve fibers, nerve tissue or the brain. The means being compatible with post-operative surgical procedures and medicaments to provide an enhancing, accelerated growth outcome when used in conjunction with such therapies or can alternatively be used alone.